The hormone atrial natriuretic peptide (ANP) is believed to play an important physiological role in protecting the organism from volume overload. Very little is known about factors which may influence ANP secretion other than stretch. We have developed a unique in vitro model by which to study ANP secretion. Isolated atria are superfused, stretched, and paced while atrial performance is recorded. ANP secretion is quantitated by RIA of timed collections of the superfusate. Using this technique the following hypotheses will be tested. 1) Calcitonin gene-related peptide (CGRP) and neuropeptide Y (NP-Y), which are located in atrial nerve fibers, influence ANP secretion. Specifically, CGRP, which activates adenylate cyclase, increases ANP secretion and NP-Y, which inhibits adenylate cyclase, blocks adenylate cyclase- dependent stimuli of ANP secretion. 2) Stretch enhances the ANP secretory response to hormonal stimuli of ANP secretion. Plasma ANP levels are elevated in congestive heart failure, yet we have found the in vitro response to stretch to be transient. This suggests that the sympathetic nervous system, working through norepinephrine, may enhance the response to stretch or vice versa. 3) Calcium is one of the second messengers of stimulated ANP secretion. A variety of inotropic agents increases ANP secretion suggesting that a rise in systolic calcium may be a part of the stimulatory signal. 4) Raising intracellular sodium increases ANP secretion. This is achieved by modifying Na-C,, exchange resulting in an increase in cytosolic calcium. 5) Activation of the Na-H antiporter increases ANP secretion by raising intracellular sodium. Completion of this project will enhance our understanding of endogenous factors which influence ANP secretion and shed light on some of the mechanisms involved. The long-term goals of this laboratory are: 1) to better understand the mechanisms of ANP secretion; 2) to apply this information to aid us in identifying drugs which positively or negatively modulate ANP secretion; and 3) to manipulate ANP secretion through drug treatment in man. Blood pressure control in hypertensive patients may improve by increasing ANP secretion, and lowering high circulating levels of ANP in congestive heart failure may lessen peripheral edema. Thus, this project may lead to important discoveries which may ultimately prove beneficial in treating cardiovascular diseases.